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Intraluminal application of angiotensin in a pressure myograph system
Başlık:
Intraluminal application of angiotensin in a pressure myograph system
Yazar:
Spiers, Angela Catherine, author.
ISBN:
9780438061460
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (96 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Advisors: John Connell.
Özet:
The renin-angiotensin (RAS) system is known to play a fundamental role in the regulation of the cardiovascular system. Many patients receive angiotensin converting enzyme inhibitor therapy (ACEi) for the treatment of hypertension, heart failure and renal disease. However, evidence indicates that in some patients the effectiveness of ACE inhibitors in blocking the RAS is limited. In these patients, following an initial decrease in circulating Angiotensin II (Ang II) levels, there is a subsequent rebound rise in plasma Ang II levels. There is evidence to suggest that enzyme pathways independent of ACE may generate Ang II. Enzymes include trypsin, chymotrypsin, cathespin G and kallilrein are capable of generating Ang II from its precursors in vitro, however, the most important non-ACE Ang II-generating enzyme is thought to be chymase. Chymase-dependent Ang II generation has been documented in the vasculature of both humans and animals. Resistance arteries are small arteries (less than 500 fam in diameter) that contribute to peripheral vascular resistance. These arteries are fundamentally important because they regulate distribution of blood by varying the size of their diameter and hence resistance to blood flow. Previous studies have documented that in these small resistance arteries, Ang II is an important regulator of vascular tone and may be produced within the vascular wall by a local RAS that exerts direct effects on endothelial and smooth muscle cells. Wire myography is an ex vivo technique which has been used extensively to examine the contractile responses of isolated human resistance arteries to Ang I, which is converted to Ang II locally, thus acting as a marker for Ang II. This allows the investigation of both active and passive properties of small arteries. A major limitation of this technique is that vasoactive agents are able to interact with receptors on either side of the vessel wall simultaneously. This is an important consideration when examining non-ACE Ang II generation, as ACE is principally located on the endothelium, whereas chymase is situated in the cytosol of mast cells within the adventitia. Thus, in vivo, Ang I may first encounter ACE, leaving limited or no precursor available for chymase-dependent Ang II formation. It is possible, therefore, that the use of wire myography to study non-ACE Ang II formation is erroneously exaggerating the importance of chymase. Pressure myography is a more physiological technique; it is an isobaric system that is more representative of conditions in vivo. By adapting an existing pressure myography system, it was hoped to investigate the release of locally generated Ang II. A DMT PI00 pressure myograph was adapted to allow intraluminal (IL) application of vasoactive drugs and develop a new method of delivering Ang I to resistance arteries. Initially, adrenoceptor agonists such as ai selective phenylephrine (PE) and non-selective norepinephrine (NE) were used to examine and compare contractile responses. Physiological salt solution (PSS) was infused to ensure that flow-induced dilatation did not compromise results. Vessels exhibited vasoconstriction to IL NE but not to IL PE. Both of these agonists caused significant contractions when added extraluminally (EL). To ensure that the pressure myograph system developed did not compromise the functioning of the endothelium, ACh mediated relaxations were investigated by adding NE to the bath, and then acetylcholine (ACh) was perfused through the lumen. A substantial vasodilatory response was observed demonstrating the expected endothelial function. To further investigate the lack of a PE-mediated response, UK 14304, a non-selective alpha2-adrencoceptor agonist was infused into the lumen. Vasoconstriction was achieved in the vessels using this agonist demonstrating the presence of functional postsynaptic alpha2 adrenoceptors in the endothelium of human subcutaneous small resistance arteries. Further experiments explored the effects of Ang I and Ang II when delivered IL. Ang I did not cause a contractile response in isolated resistance arteries when applied luminally, but did cause contraction when added EL. Similarly, Ang II caused greater contraction when added EL. This demonstrates that results obtained on the commonly used wire myograph differ substantially from results on the more physiological pressure system. The data suggest that the vasoconstrictive response to Ang II is dependent on extraluminal delivery. This raises questions about the precise role of endothelial ACE. Taken together, experiments performed in this thesis have developed and validated pressure myography and shown that methods which allow simultaneous access to both the lumen and adventitia of isolated vessels, may infer undue importance on certain receptors or signalling pathways.
Notlar:
School code: 0547
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
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XX(684881.1) | 684881-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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